Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women
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Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women. / Schizophrenia Working Group of the Psychiatric Genomics Consortium; LifeLines Cohort Study; TwinsUK ; Werge, Thomas.
I: J A M A Psychiatry, Bind 73, Nr. 5, 2016, s. 497-505.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women
AU - Mehta, Divya
AU - Tropf, Felix C
AU - Gratten, Jacob
AU - Bakshi, Andrew
AU - Zhu, Zhihong
AU - Bacanu, Silviu-Alin
AU - Hemani, Gibran
AU - Magnusson, Patrik K E
AU - Barban, Nicola
AU - Esko, Tõnu
AU - Metspalu, Andres
AU - Snieder, Harold
AU - Mowry, Bryan J
AU - Kendler, Kenneth S
AU - Yang, Jian
AU - Visscher, Peter M
AU - McGrath, John
AU - Mills, Melinda C
AU - Wray, Naomi R
AU - Lee, S Hong
AU - Andreassen, Ole A.
AU - Bramon, Elvira
AU - Bruggeman, Richard
AU - Buxbaum, Joseph D
AU - Cairns, Murray J
AU - Cantor, Rita M
AU - Cloninger, C Robert
AU - Cohen, David
AU - Crespo-Facorro, Benedicto
AU - Darvasi, Ariel
AU - Delisi, Lynn E
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Escott-Price, Valentina
AU - Freimer, Nelson B
AU - Georgieva, Lyudmila
AU - de Haan, Lieuwe
AU - Henskens, Frans A
AU - Joa, Inge
AU - Julià, Antonio
AU - Khrunin, Andrey
AU - Lerer, Bernard
AU - Limborska, Svetlana
AU - Loughland, Carmel M
AU - Macek, Milan
AU - Magnusson, Patrik K E
AU - Marsal, Sara
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - LifeLines Cohort Study
AU - TwinsUK
AU - Werge, Thomas
PY - 2016
Y1 - 2016
N2 - IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
AB - IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
KW - Adult
KW - Alleles
KW - Birth Order
KW - Cohort Studies
KW - Denmark
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Maternal Age
KW - Phenotype
KW - Pregnancy
KW - Risk
KW - Schizophrenia
KW - Journal Article
U2 - 10.1001/jamapsychiatry.2016.0129
DO - 10.1001/jamapsychiatry.2016.0129
M3 - Journal article
C2 - 27007234
VL - 73
SP - 497
EP - 505
JO - JAMA Psychiatry
JF - JAMA Psychiatry
SN - 2168-622X
IS - 5
ER -
ID: 180739134